The goal of the proposed study is to understand how endocrine cell migration cell migration and islet formation are regulated during pancreas development. Changes in islet architecture have been implicated in certain forms of diabetes and the proposed studies will help to link embryonic processes and mature islet function. We hypothesize that molecules involved in neural cell migration, including the netrin signaling molecules and extracellular matrix modulators, also guide migration of islet progenitor cells and islet formation. Our general approach is to investigate endocrine cell migration, islet formation and glucose homeostasis in mice lacking, or ectopically expressing, molecules of the netrin and matrix metalloproteinase (MMP) pathways. Several netrin ligands and receptors are found in pancreatic tissue and we propose to delineate their individual function. In vitro studiers have implicated matrix metalloproteinases and their inhibitors during islet formation. Here, we describe experiments designed to determine the individual function of these genes during pancreas development and maintenance of islet function. The specific aims of this proposal are: The first specific aim is to test if netrin ligands, molecules that guide neural cell migration, attract migrating endocrine cells from the epithelium to the location where islet formation is initiated. In collaboration with the German lab, we will determine if ectopic expression of netrin ligands in migrating islet precursors obliterates proper islet formation and, subsequently, results in impaired glucose tolerance. The second specific aim is to investigate if the corresponding netrin receptors mark endocrine precursor cells and if their function is required for proper cell migration, islet formation and maintenance of islet function. The third specific aim is to analyze if deregulation of matrix metalloproteinase activity during embryonic development inhibits islet morphogenesis. MMP's are known to regulate a variety of cellular processes, including proliferation and apoptosis. We will determine if deregulation of MMP activity in mature islets affects neogenesis or proliferation of existing beta-cells. In summary, we will explore the role of neuronal signaling components and extracellular matrix modulators for their ability to regulate pancreas organogenesis, islet formation and mature endocrine function. In collaboration with the Bell lab we will screen for mutations in these genes in people with diabetes.